Effect of Diabetes Mellitus on Pharmacokinetic and Pharmacodynamic Properties of Drugs

Abstract

The effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of drugs have been well described in experimental animal models; however, only minimal data exist for humans and the current knowledge regarding the effects of diabetes on these properties remains unclear. Nevertheless, it has been observed that the pharmacokinetics and pharmacodynamics of drugs are changed in subjects with diabetes. It has been reported that diabetes may affect the pharmacokinetics of various drugs by affecting (i) absorption, due to changes in subcutaneous adipose blood flow, muscle blood flow and gastric emptying; (ii) distribution, due to non-enzymatic glycation of albumin; (iii) biotransformation, due to regulation of enzymes/transporters involved in drug biotransformation; and (iv) excretion, due to nephropathy. Previously published data also suggest that diabetes-mediated changes in the pharmacokinetics of a particular drug cannot be translated to others. Although clinical studies exploring the effect of diabetes on pharmacodynamics are still very limited, there is evidence that disease-mediated effects are not limited only to pharmacokinetics but also alter pharmacodynamics. However, for many drugs it remains unclear whether these influences reflect diabetes-mediated changes in pharmacokinetics rather than pharmacodynamics. In addition, even though diabetes-mediated pharmacokinetics and pharmacodynamics might be anticipated, it is important to study the effect on each drug and not generalize from observed data. The available data indicate that there is a significant variability in drug response in diabetic subjects. The discrepancies between individual clinical studies as well as between ex vivo and clinical studies are probably due to (i) the restricted and focused population of subjects in clinical studies; (ii) failure to consider type, severity and duration of the disease; (iii) histopathological characteristics generally being missing; and (iv) other factors such as varying medication use, dietary protein intake, age, sex and obesity. The obesity epidemic in the developed world has also inadvertently influenced the directions of pharmacological research. This review attempts to map new information gained since Gwilt published his paper in Clinical Pharmacokinetics in 1991. Although a large body of research has been conducted and significant progress has been made, we still have to conclude that the available information regarding the effect of diabetes on pharmacokinetics and pharmacodynamics remains unclear and further clinical studies are required before we can understand the clinical significance of the effect. An understanding of diabetes-mediated changes as well as of the source of the variability should lead to the improvement of the medical management and clinical outcomes in patients with this widespread disease.

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

“…Significant effects of DM/DN on small molecules have been reported, but there are only a few studies that have evaluated the impact of DM/DN on the pharmacokinetics (PK) of antibodies (8). Although the prevalence of microalbuminuria and macroalbuminuria is significant with T2DM, only a limited number of studies have evaluated the alteration in renal elimination and urinary concentrations of proteins and macromolecules such as IgG (9,10).…”

Concentration of tacrolimus and major metabolites in kidney transplant recipients as a function of diabetes mellitus and cytochrome P450 3A gene polymorphism

“…Despite this, expression and activity of major human phase I and II drug metabolizing enzymes, under diabetes condition, was reported only in a few studies (Cheng et al ., 2001; Dostalek et al ., 2011a; Dostalek et al ., 2011b). These alterations along with other factors such as altered drug absorption, protein binding and distribution (Zini et al 1990, Dostalek et al 2012a) may have a considerable impact on the concentration of tacrolimus and its major metabolites.…”

Requirements for the formal representation of pathophysiology mechanisms by clinicians

“…Complications interfere directly with drug ADME. Specifically, relevant complications include the following departures from normal ADME function [15,16]: -Absorption: post-prandial blood pooling, stasis of stomach and gallbladder, intestinal hurry due to oversecretion or bacterial overgrowth in the small intestine, constipation, -Distribution: redistribution of blood volume, altered drug-to-plasma protein binding, and changed volumes of drug distribution, -Metabolism: the ability of the liver to produce plasma protein (e.g. albumin) and to metabolize drugs is impaired, as well as -Elimination: impaired biliary and renal function that impact on drug biotransformation and excretion, respectively.…”